A number of drugs which inhibit cholinergic neurotransmission do so through interactions with the ion channel associated with the nicotinic acetylcholine receptor. Phencyclidine and its analogs are among the most potent in this regard. Preliminary biophysical and biochemical studies also indicate that anticholinergic psychotomimetic glycolate esters and certain opiate agonists and antagonists interact directly with synaptic ion channels. In the proposed studies, the ion channel will be evaluated as a site of action for these drugs using radiolabeled ligand binding techniques. Electric organs from Torpedo will serve as a plentiful and readily assessible source of cholinergic synapses. Six radiolabeled phencyclidines and glycolate esters have been prepared and will be evaluated for direct use as biochemical probes for the ion channel. We have demonstrated that several functional states of the receptor-ion channel complex, including resting, activated, desensitized and blocked, are evident in the kinetics of ion channel binding. This affords a means for investigating allosteric interactions between the receptor and ion channel, as well as providing biochemical criteria for the identification of ion channel binding sites. The biochemical nature of the ion channel and the nature of its coupling to the receptor will be studied by monitoring the effects of enzymes, pH, chaotropes, temperatures, ions and controlled membrane dissaggregation on ion channel binding. This study should provide information of the mechanisms underlying drug action in the nervous system.